Platform adaptive trial of novel antivirals for early treatment of COVID-19 In the community (PANORAMIC): protocol for a randomised, controlled, open-label, adaptive platform trial of community novel antiviral treatment of COVID-19 in people at increased risk of more severe disease

Introduction: There is an urgent need to determine the safety, effectiveness and cost-effectiveness of novel antiviral treatments for COVID-19 in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. // Methods and analysis: PANORAMIC is a UK-wide, open-label, prospective, adaptive, multiarm platform, randomised clinical trial that evaluates antiviral treatments for COVID-19 in the community. A master protocol governs the addition of new antiviral treatments as they become available, and the introduction and cessation of existing interventions via interim analyses. The first two interventions to be evaluated are molnupiravir (Lagevrio) and nirmatrelvir/ritonavir (Paxlovid). Eligibility criteria: community-dwelling within 5 days of onset of symptomatic COVID-19 (confirmed by PCR or lateral flow test), and either (1) aged 50 years and over, or (2) aged 18–49 years with qualifying comorbidities. Registration occurs via the trial website and by telephone. Recruitment occurs remotely through the central trial team, or in person through clinical sites. Participants are randomised to receive either usual care or a trial drug plus usual care. Outcomes are collected via a participant-completed daily electronic symptom diary for 28 days post randomisation. Participants and/or their Trial Partner are contacted by the research team after days 7, 14 and 28 if the diary is not completed, or if the participant is unable to access the diary. The primary efficacy endpoint is all-cause, non-elective hospitalisation and/or death within 28 days of randomisation. Multiple prespecified interim analyses allow interventions to be stopped for futility or superiority based on prespecified decision criteria. A prospective economic evaluation is embedded within the trial. // Ethics and dissemination: Ethical approval granted by South Central–Berkshire REC number: 21/SC/0393; IRAS project ID: 1004274. Results will be presented to policymakers and at conferences, and published in peer-reviewed journals. // Trial registration number: ISRCTN30448031; EudraCT number: 2021-005748-31

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Molnupiravir Plus Usual Care Versus Usual Care Alone as Early Treatment for Adults with COVID-19 at Increased Risk of Adverse Outcomes (PANORAMIC): Preliminary Analysis from the United Kingdom Randomised, Controlled Open-Label, Platform Adaptive Trial

Background: The safety, effectiveness and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, in patients in the community who are multiply-vaccinated and at increased risk of morbidity and mortality from COVID-19, has not been established. We aimed to determine whether molnupiravir added to usual care reduced hospital admissions/deaths among people at higher risk from COVID-19, and here report our preliminary analyses. Methods: Participants in this UK multicentre, open-label, adaptive, multi-arm, platform, randomised controlled trial were aged ≥50, or ≥18 years with comorbidities, and unwell ≤5 days with confirmed COVID-19 in the community, and were randomised to usual care or usual care plus molnupiravir (800mg twice daily for 5 days). The primary outcome measure was all-cause hospitalisation/death within 28 days, analysed using Bayesian models. The main secondary outcome measure was time to first self-reported recovery. A sub-set of participants in each group were assessed for the virology primary outcome measure of day seven SARS-CoV-2 viral load. Trial registration: ISRCTN30448031 Findings: Between December 8, 2021 and April 27, 2022, 25783 participants were randomised to molnupiravir plus usual care (n=12821) or usual care alone (n=12962). Mean (range) age of participants was 56·6 years (18 to 99), 58·6% were female, and 99% had at least one dose of a SARS-CoV-2 vaccine. The median duration of symptoms prior to randomisation was two days (IQR 1 – 3), the median number of days from symptom onset to starting to take the medication was three days (IQR 3 – 4), 87% (11109/11997) received their medication within five days of symptom onset, and 95·4% (n=11857) of participants randomised to molnupiravir reported taking molnupiravir for five days. Primary outcome measure data were available in 25000 (97%) participants and included in this analysis. 103/12516 (0·8%) hospitalisations/deaths occurred in the molnupiravir group versus 96/12484 (0·8%) in usual care alone with a posterior probability of superiority of 0·34 (adjusted odds ratio 1·061 (95% Bayesian credible interval [BCI]) 0·80 to 1·40). Estimates were similar for all subgroups. The observed median (IQR) time-to-first-recovery from randomisation was 9 (5–23) days in molnupiravir and 15 (7–not reached) days in usual care. There was an estimated benefit of 4·2 (95% BCI: 3·8 – 4·6) days in time-to-first-recovery (TTR) giving a posterior probability of superiority of >0·999 (estimated median TTR 10·3 [10·2 – 10·6] days vs 14·5 [14·2 – 14·9] days respectively; hazard ratio [95% BCI], 1·36 [1·3–1·4] days), which met the pre-specified superiority threshold. On day 7, SARS-CoV-2 virus was below detection levels in 7/34 (21%) of the molnupiravir group, versus 1/39 (3%) in the usual care group (p=0.039), and mean viral load was lower in the molnupiravir group compared with those receiving usual care [(SD) of log10(viral load) 3·82 (1·40) in the molnupiravir group and 4.93 (1·38) in the usual care group, (P<0·001)]. 59 (0·4%) participants experienced serious adverse events in the molnupiravir group and 52 (0·4%) in usual care. Interpretation: In this preliminary analysis, we found that molnupiravir did not reduce already low hospitalisations/deaths among higher risk, vaccinated adults with COVID-19 in the community, but resulted in faster time to recovery, and reduced viral detection and load. Funding: This project is funded by the NIHR (NIHR135366). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care

Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial

Background: The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population. Methods: PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older—or aged 18 years or older with relevant comorbidities—and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (&lt;50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031. Findings: Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81–1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir. Interpretation: Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community

Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial

BackgroundThe safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population.MethodsPANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older—or aged 18 years or older with relevant comorbidities—and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031.FindingsBetween Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81–1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir.InterpretationMolnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community

The Potential Role for Securitizing Public Sector Revenue Flows

Since the mid-1980s, the securitization of future flow receivables has grown in importance as a financing alternative for the public sector. In a world of perfect capital markets, there appears to be little rationale-in terms of reducing the average cost of public sector financing-to resort to secured borrowing. However, for many developing countries, financial markets are far from perfect. In particular, there may be an important role for secured financing where increased uncertainty or financial market volatility leads to credit rationing driven by information asymmetries. Secured financing, however, does not provide a free lunch. Such arrangements subordinate existing and future creditors and, as a result, may raise the cost of future borrowing. In addition, high transaction costs, the thin market in secured instruments, the risk of legal challenges, and reduced budget and debt management flexibility may offset the cost advantage of public sector securitization.

Tax Incentives in the Philippines

The Philippines is faced with a policy dilemma in the area of corporate taxation. On the one hand, the country has, over the past few years, witnessed a decline in revenue as a share of output. On the other, it is operating in an increasingly competitive regional market for foreign direct investment. In order to remain competitive, the Philippines offers a broad array of fiscal incentives to entice inward investment and pursue the country''s development goals. This paper looks at the fiscal incentives available in the Philippines, compares them with those available in the ASEAN region, and with the evidence on the efficacy of tax incentives in a global context. The paper provides some broad conclusions on the use of the various forms of tax incentives in the Philippines and on their administration.

Structural Balances and All That

Structural indicators of a country''s fiscal position are regularly used as estimates of both discretionary changes in fiscal policy and the effect of fiscal policy on aggregate demand. This paper looks at such indicators and evaluates, from a theoretical standpoint and from empirical case studies, their usefulness in measuring the size of discretionary policy action or fiscal demand stimulus. Two propositions are examined in detail: first, that the change in the primary structural balance provides a better indicator of discretionary fiscal policy than does the change in the primary balance; and second, that the change in the structural balance is a good indicator of the demand stimulus arising from changes in the fiscal position. In addition, the paper discusses measurement problems relating to structural balances and the use of the fiscal impulse as an alternative to structural balances.

Assessing Fiscal Sustainability in Theory and Practice

The main purpose of this paper is to provide an overview of approaches to assessing fiscal sustainability. It summarizes the general analytical background, focusing on the present value budget constraint, which is the benchmark against which solvency is determined, tests of sustainability (including sustainability indicators), and sustainability and uncertainty. The paper then looks at the way in which fiscal sustainability has been assessed in different types of IMF work. Finally the link between fiscal and external sustainability is discussed.Budget deficits;Economic models;fiscal sustainability, fiscal policy, debt ratio, budget constraint, primary deficit, government debt, external debt, net debt, debt service, public debt, fiscal adjustment, tax ratio, fiscal policies, debt sustainability, current account, fiscal position, debt stock, public external debt, fiscal balances, fiscal vulnerability, debt relief, domestic currency, fiscal balance, external debt service, traditional debt relief mechanisms, current account deficit, fiscal deficits, government solvency, fiscal deficit, ratio of debt, relief mechanisms, external liabilities, primary expenditure, fiscal surpluses, government deficits, net external liabilities, public finances, government revenue, fiscal transparency, budget balance, debt relief mechanisms, fiscal surplus, domestic debt, traditional debt relief, foreign debt, sustainable fiscal policy, debt dynamics, taxation, fiscal affairs department, fiscal measures, fiscal outcomes, public sector debt, sovereign debt, fiscal revenues, debt ratios, debt structure, external debt sustainability, fiscal standpoint, government budget, account deficits, debt service to exports, government budget deficits, debt burden, fiscal affairs, budget constraints, primary fiscal deficit, budget deficit, debt problem, fiscal indicators, current account deficits, fiscal criterion, domestic financial markets, fiscal data, stock of debt, excessive deficits, fiscal developments, ratios of debt, fiscal scenario, annual budget, government spending, fiscal accounts, future fiscal deficits, fiscal program